Tissue-Specific Effects of Chlorpyrifos on Carboxylesterase and Cholinesterase Activity in Adult Rats: Anin Vitroandin VivoComparison

Chanda, Sushmita

doi:10.1006/faat.1997.2329

Cited by 131 publications

(6 citation statements)

References 32 publications

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“…Although the CPF dosing regimen that we used (2.5 mg/kg, 7 days) and the assessment of immune effects at a single time point after LPS challenge might have limited us from observing CPF-dependent alterations in lung immunity, an alternative explanation is that Ces isoforms in lung provide an important protective function that prevents CPF-mediated immunotoxic effects because of their ability to neutralize reactive oxons. ,, This is supported by the observation that Ces isoforms were the main serine hydrolases inactivated in lung (Figure ). Studies in guinea pigs and rats also suggested that the lung is an important site for the detoxification of OPs. , Interestingly, our data indicated Ces1c was inhibited by CPF in mice of all ages.…”

Section: Discussionmentioning

confidence: 87%

Effects of Chlorpyrifos on Serine Hydrolase Activities, Lipid Mediators, and Immune Responses in Lungs of Neonatal and Adult Mice

Szafran

Borazjani

Seay

et al. 2021

Chem. Res. Toxicol.

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Chlorpyrifos (CPF) is an organophosphate (OP) pesticide that causes acute toxicity by inhibiting acetylcholinesterase (AChE) in the nervous system. However, endocannabinoid (eCB) metabolizing enzymes in brain of neonatal rats are more sensitive than AChE to inhibition by CPF, leading to increased levels of eCBs. Because eCBs are immunomodulatory molecules, we investigated the association between eCB metabolism, lipid mediators, and immune function in adult and neonatal mice exposed to CPF. We focused on lung effects because epidemiologic studies have linked pesticide exposures to respiratory diseases. CPF was hypothesized to disrupt lung eCB metabolism and alter lung immune responses to lipopolysaccharide (LPS), and these effects would be more pronounced in neonatal mice due to an immature immune system. We first assessed the biochemical effects of CPF in adult mice (≥8 weeks old) and neonatal mice after administering CPF (2.5 mg/kg, oral) or vehicle for 7 days. Tissues were harvested 4 h after the last CPF treatment and lung microsomes from both age groups demonstrated CPF-dependent inhibition of carboxylesterases (Ces), a family of xenobiotic and lipid metabolizing enzymes, whereas AChE activity was inhibited in adult lungs only. Activity-based protein profiling (ABPP)-mass spectrometry of lung microsomes identified 31 and 32 individual serine hydrolases in neonatal lung and adult lung, respectively. Of these, Ces1c/Ces1d/Ces1b isoforms were partially inactivated by CPF in neonatal lung, whereas Ces1c/Ces1b and Ces1c/BChE were partially inactivated in adult female and male lungs, respectively, suggesting age- and sex-related differences in their sensitivity to CPF. Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) activities in lung were unaffected by CPF. When LPS (1.25 mg/kg, i.p.) was administered following the 7-day CPF dosing period, little to no differences in lung immune responses (cytokines and immunophenotyping) were noted between the CPF and vehicle groups. However, a CPF-dependent increase in the amounts of dendritic cells and certain lipid mediators in female lung following LPS challenge was observed. Experiments in neonatal and adult Ces1d – /– mice yielded similar results as wild type mice (WT) following CPF treatment, except that CPF augmented LPS-induced Tnfa mRNA in adult Ces1d – /– mouse lungs. This effect was associated with decreased expression of Ces1c mRNA in Ces1d – /– mice versus WT mice in the setting of LPS exposure. We conclude that CPF exposure inactivates several Ces isoforms in mouse lung and, during an inflammatory response, increases certain lipid mediators in a female-dependent manner. However, it did not cause widespread altered lung immune effects in response to an LPS challenge.

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Section: Discussionmentioning

confidence: 87%

Effects of Chlorpyrifos on Serine Hydrolase Activities, Lipid Mediators, and Immune Responses in Lungs of Neonatal and Adult Mice

Szafran

Borazjani

Seay

et al. 2021

Chem. Res. Toxicol.

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“…In addition, baseline plasma acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and carboxylesterase (CE) activity levels were measured. These esterases bind to CWNAs, and numerous studies report sex differences in baseline levels (Leeuwin, 1965; Schmidt and Schmidt, 1978; Illsley and Lamartiniere, 1981; Sterri and Fonnum, 1989; Chanda et al , 1997), which may affect sensitivity to sarin. If lethality significantly fluctuates throughout the estrous cycle in female rats, consideration should be taken in future studies to reduce variability by controlling for hormonal state.…”

Section: Introductionmentioning

confidence: 99%

Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle

Smith¹,

Wright²,

Garcia³

et al. 2015

Toxicology and Applied Pharmacology

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Chemical warfare nerve agents (CWNAs) are highly toxic compounds that cause a cascade of symptoms and death, if exposed casualties are left untreated. Numerous rodent models have investigated the toxicity and mechanisms of toxicity of CWNAs, but most are limited to male subjects. Given the profound physiological effects of circulating gonadal hormones in female rodents, it is possible that the daily cyclical fluctuations of these hormones affect females’ sensitivity to the lethal effects of CWNAs, and previous reports that included female subjects did not control for the stage of the hormonal cycle. The aim of the current study was to determine the 24-hour median lethal dose (LD50) of the CWNA sarin in male, ovariectomized (OVEX) female, and female rats during different stages of the estrous cycle (diestrus, proestrus, and estrus). Additionally, baseline activity levels of plasma acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were measured to determine differences among the groups. Results indicated that females in proestrus had a significantly higher LD50 of sarin compared to OVEX and estrous females. Although some sex differences were observed in the activity levels of plasma esterases, they were not consistent and likely not large enough to significantly affect the LD50s. These results suggest that hormonal cyclicity can influence the outcome of CWNA-related studies using female rodents, and that this variability can be minimized by controlling for the stage of the cycle. Additional research is necessary to determine the precise mechanism of the observed differences because it is unlikely to be solely explained by plasma esterase activity.

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“…CPF-oxon is enzymatically hydrolyzed by A-esterases such as paraoxonase 1 (PON-1) (Pond et al 1998; Sultatos and Murphy 1983) to form the detoxified metabolites diethylphosphate (DEP) and 3,5,6 trichloropyridinol (TCPy). The inhibition of B-esterase by CPF-oxon can also result in the formation of DEP and TCPy (Chanda et al 1997). The parent compound CPF can also be metabolized by CYP enzymes to form diethylthiophosphate (DETP) and TCPy (a CPF-specific biomarker of exposure) (Ma and Chambers 1994), which are readily excreted in urine (Nolan et al 1984).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of chlorpyrifos in adult male Long-Evans rats following repeated subcutaneous exposure to chlorpyrifos

et al. 2011

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Chlorpyrifos (CPF) is a commonly used organophosphorus pesticide. Several pharmacokinetic and pharmacodynamic studies have been conducted in rats in which CPF was administered as a single bolus dose. However, there is limited data regarding the pharmacokinetics and pharmacodynamics following daily exposure. Since occupational exposures often consist of repeated, daily exposures, there is a need to evaluate the pharmacokinetics and pharmacodynamics of CPF under exposure conditions which more accurately reflect real world human exposures. In this study, the pharmacokinetics and pharmacodynamics of CPF were assessed in male Long Evans rats exposed daily to CPF (0, 3 or 10mg/kg/day, s.c. in peanut oil) over a ten day study period. Throughout the study, multiple pharmacokinetic (urinary TCPy levels and tissue CPF and metabolite levels) and pharmacodynamic (blood and brain AChE activity) determinants were measured. Average blood AChE activity on day ten was 54 and 33 percent of baseline among animals in the 3 and 10mg/kg/day CPF treatment groups, respectively, while average brain AChE activity was 67 and 28 percent of baseline. Comparable dose-response relationships between brain AChE inhibition and blood AChE inhibition, suggests that blood AChE activity is a valid biomarker of brain AChE activity. The pharmacokinetic and pharmacodynamic measures collected in this study were also used to optimize a rat physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for multiple s.c. exposures to CPF based on a previously published rat PBPK/PD model for CPF following a single bolus injection. This optimized model will be useful for determining pharmacokinetic and pharmacodynamic responses over a wide range of doses and durations of exposure, which will improve extrapolation of results between rats and humans.

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Tissue-Specific Effects of Chlorpyrifos on Carboxylesterase and Cholinesterase Activity in Adult Rats: Anin Vitroandin VivoComparison

Cited by 131 publications

References 32 publications

Effects of Chlorpyrifos on Serine Hydrolase Activities, Lipid Mediators, and Immune Responses in Lungs of Neonatal and Adult Mice

Effects of Chlorpyrifos on Serine Hydrolase Activities, Lipid Mediators, and Immune Responses in Lungs of Neonatal and Adult Mice

Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle

Pharmacokinetics and pharmacodynamics of chlorpyrifos in adult male Long-Evans rats following repeated subcutaneous exposure to chlorpyrifos

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